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==Crystal structure of CBP bromodomain liganded with UMB298 (compound 23)== | ==Crystal structure of CBP bromodomain liganded with UMB298 (compound 23)== | ||
<StructureSection load='7kpy' size='340' side='right'caption='[[7kpy]]' scene=''> | <StructureSection load='7kpy' size='340' side='right'caption='[[7kpy]], [[Resolution|resolution]] 1.70Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KPY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KPY FirstGlance]. <br> | <table><tr><td colspan='2'>[[7kpy]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KPY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KPY FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7kpy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kpy OCA], [https://pdbe.org/7kpy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kpy RCSB], [https://www.ebi.ac.uk/pdbsum/7kpy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kpy ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=WU1:2-[2-(3-chloranyl-4-methoxy-phenyl)ethyl]-~{N}-cyclohexyl-7-(3,5-dimethyl-1,2-oxazol-4-yl)imidazo[1,2-a]pyridin-3-amine'>WU1</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CREBBP ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Histone_acetyltransferase Histone acetyltransferase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.48 2.3.1.48] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7kpy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kpy OCA], [https://pdbe.org/7kpy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kpy RCSB], [https://www.ebi.ac.uk/pdbsum/7kpy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kpy ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The use of epigenetic bromodomain inhibitors as anticancer therapeutics has transitioned from targeting bromodomain extraterminal domain (BET) proteins into targeting non-BET bromodomains. The two most relevant non-BET bromodomain oncology targets are cyclic AMP response element-binding protein (CBP) and E1A binding protein P300 (EP300). To explore the growing CBP/EP300 interest, we developed a highly efficient two-step synthetic route for dimethylisoxazole-attached imidazo[1,2-a]pyridine scaffold-containing inhibitors. Our efficient two-step reactions enabled high-throughput synthesis of compounds designed by molecular modeling, which together with structure-activity relationship (SAR) studies facilitated an overarching understanding of selective targeting of CBP/EP300 over non-BET bromodomains. This led to the identification of a new potent and selective CBP/EP300 bromodomain inhibitor, UMB298 (compound 23, CBP IC50 72 nM and bromodomain 4, BRD4 IC50 5193 nM). The SAR we established is in good agreement with literature-reported CBP inhibitors, such as CBP30, and demonstrates the advantage of utilizing our two-step approach for inhibitor development of other bromodomains. | |||
Development of Dimethylisoxazole-Attached Imidazo[1,2-a]pyridines as Potent and Selective CBP/P300 Inhibitors.,Muthengi A, Wimalasena VK, Yosief HO, Bikowitz MJ, Sigua LH, Wang T, Li D, Gaieb Z, Dhawan G, Liu S, Erickson J, Amaro RE, Schonbrunn E, Qi J, Zhang W J Med Chem. 2021 May 13;64(9):5787-5801. doi: 10.1021/acs.jmedchem.0c02232. Epub , 2021 Apr 19. PMID:33872011<ref>PMID:33872011</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7kpy" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Histone acetyltransferase]] | |||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Bikowitz M]] | [[Category: Bikowitz, M]] | ||
[[Category: Schonbrunn E]] | [[Category: Schonbrunn, E]] | ||
[[Category: Drug development]] | |||
[[Category: Epigenetic]] | |||
[[Category: Inhibitor]] | |||
[[Category: Multi domain protein]] | |||
[[Category: Transcription]] | |||
Revision as of 12:29, 26 May 2021
Crystal structure of CBP bromodomain liganded with UMB298 (compound 23)Crystal structure of CBP bromodomain liganded with UMB298 (compound 23)
Structural highlights
Publication Abstract from PubMedThe use of epigenetic bromodomain inhibitors as anticancer therapeutics has transitioned from targeting bromodomain extraterminal domain (BET) proteins into targeting non-BET bromodomains. The two most relevant non-BET bromodomain oncology targets are cyclic AMP response element-binding protein (CBP) and E1A binding protein P300 (EP300). To explore the growing CBP/EP300 interest, we developed a highly efficient two-step synthetic route for dimethylisoxazole-attached imidazo[1,2-a]pyridine scaffold-containing inhibitors. Our efficient two-step reactions enabled high-throughput synthesis of compounds designed by molecular modeling, which together with structure-activity relationship (SAR) studies facilitated an overarching understanding of selective targeting of CBP/EP300 over non-BET bromodomains. This led to the identification of a new potent and selective CBP/EP300 bromodomain inhibitor, UMB298 (compound 23, CBP IC50 72 nM and bromodomain 4, BRD4 IC50 5193 nM). The SAR we established is in good agreement with literature-reported CBP inhibitors, such as CBP30, and demonstrates the advantage of utilizing our two-step approach for inhibitor development of other bromodomains. Development of Dimethylisoxazole-Attached Imidazo[1,2-a]pyridines as Potent and Selective CBP/P300 Inhibitors.,Muthengi A, Wimalasena VK, Yosief HO, Bikowitz MJ, Sigua LH, Wang T, Li D, Gaieb Z, Dhawan G, Liu S, Erickson J, Amaro RE, Schonbrunn E, Qi J, Zhang W J Med Chem. 2021 May 13;64(9):5787-5801. doi: 10.1021/acs.jmedchem.0c02232. Epub , 2021 Apr 19. PMID:33872011[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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